The principal objective of the proposed research is to clarify the participation and interaction of several metabolically linked chemicals which mediate locally the regulation of blood flow in the coronary circulation. The chemical factors which are the most likely candidates are oxygen, potassium ions, hydrogen ions (or carbon dioxide), and adenosine and its mononucleotides. The model used to investigate the role of these chemicals will be the isolated, Ringer's perfused guinea pig heart. A central component of the experimental design is a two heart perfusion system; one heart will serve as a bioassay organ for the vasoactivity of the effluent of the first heart. The specific goals of this project are to satisfactorily answer several controversial, but fundamental questions: 1) Do low levels of O2 and pH, as observed during ischemia, interact to evoke vasodilation? 2) Are increases in K ions and osmolality also involved in this response, at least initially? 3) Does the H ion or CO2 per se produce vasodilation, and what is the basis for the transient vasoconstriction induced by CO2? 4) Does O2 act directly or indirectly through release of adenyl compounds to effect vasodilation? 5) Which of the adenyl compounds is released during ischemia, and which can survive transit through the coronary vasculature? Such added information will help to advance our knowledge of the mechanism of action and interaction of locally delivered and elaborated chemicals on adjusting coronary blood flow in response to ischemia, occlusion and increased myocardial function. It is believed that the findings elicited from the investigations outlined in this proposal will contribute, not only to a better understanding of the normal physiological processes controlling the blood supply to the heart, but also to establishment of a more comprehensive base of information on which to treat diseases of the coronary circulation rationally.